ROLE OF APPENDIX AND GALT IN DEVELOPMENT OF THE PRIMARY HUMAN IMMUNE REPERTOIRE

我们在兔身上的研究表明，年轻的阑尾是产生保护性抗体的细胞的重要发育部位。兔阑尾的功能与法布里西乌斯鸡的法氏囊相似。幼兔阑尾B淋巴细胞快速生长扩增，出现阳性和阴性选择事件。我们认为，在阑尾选择中幸存下来的细胞播种于外周淋巴系统，并经历自我更新以维持最初的谱系。在兔身上的数据使我们研究了人的阑尾和GALT在人的免疫谱系和粘膜免疫中的作用。我们比较了正常人和兔阑尾生发中心(GC)在不同年龄的发育情况。在人和兔的阑尾中，我们发现淋巴滤泡在出生时才刚刚开始形成。生发中心在人的1个月左右和兔的阑尾1周时出现。大多数淋巴组织的发育发生在人的第一年内，在兔的阑尾的前12周内。成年后，人和兔的阑尾淋巴组织开始萎缩。卵泡变小，数量减少，结缔组织和平滑肌增多。阑尾并没有完全变大；75岁或以上的人和6岁和7岁的兔子标本中仍有5个生发中心。人的阑尾具有哺乳动物法氏囊的一些特征；它是幼年的富含B细胞的器官，滤泡和GC的形态随着年龄的变化而变化。人的阑尾在许多方面与兔阑尾、禽法氏囊和绵羊回肠Peyer‘s补片相似，但也有一些不同之处。人阑尾发育过程中的GC结构和相对GC T细胞密度与兔阑尾和鸡法氏囊不同，提示人阑尾更类似于外周淋巴器官，而不是中枢淋巴器官。然而，外周淋巴器官可能具有某些中枢淋巴功能。这是否适用于人类的阑尾和其他高尔特，值得进一步研究。对抗体重链和轻链编码基因序列的分子研究正在进行中(参见Z01 AI00226-19Li)，以进一步调查人类的阑尾是否起到了作为主要淋巴器官的作用(J.Dasso等，2000)。一项名为#OH99-I-N026的临床研究方案被国家儿童医学中心的IRBs和美国国立卫生研究院的NIAID审查和批准。我于2000年7月29日终止了这项研究，因为累积的患者数量较少，而且我们无法完成本应分析口服脊髓灰质炎疫苗反应的研究。一篇论文描述了开发的制备和分析患者样本的方法和一些初步结果正在准备中(J.Dasso等人，MS正在准备中)。

Our studies in the rabbit have shown that the young appendix is an important site of development of the cells destined to produce protective antibodies. The rabbit appendix has functions similar to those of the avian bursa of Fabricius. In the young rabbit, there is rapid growth and expansion of B lymphocytes in the appendix, and positive and negative selection events occur. We believe that the cells that survive selection in the appendix seed the peripheral lymphoid system and undergo self renewal to maintain the primary repertoire. The data on rabbit led us to study the role of human appendix and GALT in development of the human immune repertoire and mucosal immunity. We compared development of normal human appendix germinal centers (GC) with rabbit appendix GC development at different ages. In both human and rabbit appendix, we found that lymphoid follicles were just beginning to form at birth. Germinal centers became evident at about 1 month in human and at 1 week in rabbit appendix. Most lymphoid development occurred within the first year in the human and within the first 12 weeks in the rabbit appendix. Lymphoid tissue began to atrophy by adulthood in both human and rabbit appendix. The follicles became smaller and fewer in number whereas the connective tissue and smooth muscle increased. The appendix did not entirely involute; germinal centers were still present in 5 human samples from individuals 75 years or older and in 6- and 7 yr-old rabbit specimens. The human appendix shares some characteristics of a "mammalian bursa equivalent"; it is a B-cell rich organ in the young and the morphology of the follicles and GC changes with age. The human appendix is similar in many respects to the rabbit appendix, avian bursa and sheep ileal Peyer's patch, yet several differences exist. The GC structure and relative GC T-cell density of the human appendix throughout development differs from that of the rabbit appendix and chicken bursa which could indicate that human appendix is more similar to a peripheral than central lymphoid organ. However, it is possible that peripheral lymphoid organs share some central lymphoid function. Whether this is true for the human appendix and other GALT warrants further investigation. Molecular studies of sequences of genes encoding antibody heavy and light chain are in progress (see Z01 AI00226-19 LI) to further investigate whether the appendix of man plays any role as a primary lymphoid organ.(J. Dasso et al., 2000).A clinical research protocol (#OH99-I-N026) entitled, "Effect of Appendectomy on Mucosal Immunity in Children" was reviewed and approved by the IRBs of Children's National Medical Center, and NIAID, NIH. I terminated this study as of July 29, 2000 because of low numbers of patients accrued and our inability to carry through the arm of the study that would have analyzed responses to oral polio vaccine. A paper describing the methods developed to prepare and assay patient samples and some preliminary results is in preparation (J. Dasso et al., ms in preparation).